The long term goal of the research is to further understand the regulation of nitrogen flow to urea synthesis in humans. A specific focus is on patients with genetic disorders of the urea cycle (UCDs). Currently funded research has shown that inviduals who are heterozygotic for ornithine transcarbamylase and arginino succinic acid synthase deficiency appear to have a partial block in their ability to use glutamine as a nitrogen source for urea synthesis, and that they rely on the hepatic clearance of ammonia generated in the gut to maintain their post prandial N homeostasis. Preliminary results suggest that the administration of sodium phenyl butyrate, a common treatment for UCDs, disrupts branched chain amino acid metabolism. We argue therefore that because of the importance of leucine to protein metabolic regulation, treatment with phenyl butyrate not only diverts N away from urea synthesis, but compromises the regulation of body protein turnover. We hypothesize: Hypothesis 1: Phenyl butyrate, given at therapeutic levels, specifically diverts branched chain amino nitrogen towards glutamine production and away from net tissue protein synthesis. Hypothesis 2: Phenyl butyrate treatment thus inhibits the ability of the body to maintain nitrogen equilibrium, particularly at the restricted protein intakes used in the treatment of UCDs and other metabolic diseases; Hypothesis 3: Patients with UCDs, who are concurrently treated with phenylbutyrate and a low protein diet, will benefit from dietary supplements of branched chain amino acids.To test these hypotheses, we will use stable isotopic tracers of leucine, glutamine, phenylalanine and urea metabolism in studies in normal subjects and individuals with partial or complete defects in urea synthesis. The specific aims will be: Specific aim 1: Determine, in control subjects and heterozygotic carriers of UCDs, the effect of phenyl butyrate on urea, glutamine and branched chain amino acid metabolism. Quantify its effects on body protein turnover. Specific aim 2: Quantify whole body protein turnover and balance in patents with null urea cycle activity who are receiving the conventional regime of phenyl butyrate and a low protein diet. Specific aim 3: Determine the effect of oral branched chain-amino acid supplements on protein, leucine and glutamine metabolism in urea-cycle patients and controls who are receiving phenyl butyrate.The main objective therefore is to use the new clinically oriented information on the regulation of human nitrogen homeostasis, to develop novel nutritional approaches to the treatment of UCDs and other metabolic diseases. In addition it is anticipated that the results will benef it other individuals who have compromised protein metabolism.